Prevalence, chronicity, burden and borders of bipolar disorder

Journal of Affective Disorders 148 (2013) 161–169

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Review

Prevalence, chronicity, burden and borders of bipolar disorder Andrea Fagiolini a,n, Rocco Forgione b, Mauro Maccari c, Alessandro Cuomo a, Benedetto Morana d, Mario Catena Dell’Osso b, Francesca Pellegrini a, Alessandro Rossi e a

University of Siena, Department of Molecular Medicine and Clinical (DAI) Department of Mental Health, Viale Bracci 1, Siena 53100, Italy Private Practice c Community Health Trust Service AUSL 7, Siena, Italy d Casa di Cura Morana, Contrada Dara 744/D, 91025 Marsala (TP), Italy e DISCAB - Section of Psychiatry and Neurosciences, University of L’Aquila, Italy b

a r t i c l e i n f o

abstract

Article history: Received 9 October 2012 Received in revised form 6 February 2013 Accepted 6 February 2013 Available online 7 March 2013

Bipolar disorder (BD) has traditionally been thought of as an episodic condition, characterized by periods of hypomania/mania and depression. However, evidence is accumulating to suggest that this condition is associated with significant chronicity. For a large proportion of patients with BD, residual, sub-syndromal symptoms persist between major syndromal episodes, and studies have shown that many patients with bipolar disorder are symptomatic for approximately 50% of the time over follow-up periods of greater than 10 years. Moreover, while the prevalence of BD has been estimated to be around 1–2%, there is growing evidence that this may be a substantial underestimation. There are a number of reasons for this potential underestimation, including difficulties in diagnosis. Adding to the burden of BD is the issue of comorbidity, with an increased prevalence of many chronic conditions in those with a primary diagnosis of BD. Conversely, for many patients with chronic conditions, both medical and psychiatric, BD frequently exists as a comorbid secondary diagnosis. This issue of comorbidity complicates estimates of use of pharmaceutical agents for BD, such as mood stabilizers, which are known to be used off-label in conditions such as borderline personality or substance use disorder. We speculate that such off-label prescribing may not be truly off-label but may be instead fully justified by an overlooked secondary diagnosis of BD. Finally, we discuss the association of bipolar disorder with a significant economic burden, to the individual and to society, both due to the direct costs of medical expenditure and indirect costs such as loss of productivity and increased mortality. & 2013 Elsevier B.V. All rights reserved.

Keywords: Bipolar disorders Chronicity Economic burden Prevalence Treatment

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 What is the true prevalence of bipolar disorder? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Delayed diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Comorbidities in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Off-label prescription of bipolar disorder medications may indicate a higher than estimated prevalence of BD . . . . . . . . . . . . . . . . . . . . . . . 163 Premorbid personality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Prodromal, residual and sub-syndromal symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 The natural course of bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Implications for treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 The cost of bipolar disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 10.1. Comorbidity increases costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 10.2. Occupational burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Long term outcomes and excess mortality in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Role of funding source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

n Correspondence to: Department of Mental Health and Molecular Medicine, Division of Psychiatry, School of Medicine, University of Siena, Viale Bracci 1, Siena 53100, Italy. Tel.: þ 39 0577 233294; fax: þ 39 0577 233451. E-mail address: [email protected] (A. Fagiolini).

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.02.001

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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

1. Introduction Bipolar disorder is a clinically severe, episodic, lifelong mood disorder (Fagiolini et al., 2009; Judd et al., 2002; Perlis et al., 2006; Solomon et al., 1995). The traditional defining feature of bipolar disorder is the occurrence of episodes of mania or hypomania alternating, or occurring currently with, depressive episodes (Oswald et al., 2007). Episodes in bipolar disorder are usually separated by periods of recovery, with return to normal function, but recurrence rates are high (Oswald et al., 2007; Prien and Kocsis, 1995). However, the course of bipolar disease is not entirely clear and recent research is suggesting that patients with bipolar disorder experience symptoms over much longer periods than previously thought (Judd et al., 2002). Moreover, there exists substantial evidence that, for many people, residual symptoms are present between episodes (Benazzi, 2001; Kaya et al., 2007; Keitner et al., 1996). The prevalence of bipolar I disorder in the general population has been estimated to be between 1% and 2% (Oswald et al., 2007; Pini et al., 2005), although the 2000 National Depressive and ManicDepressive Association survey provided an estimate of the prevalence of bipolar I and II in the US of 3.4% (Berk et al., 2006). It is likely that the true prevalence of bipolar disorder is higher than reported, as there is increasing evidence that bipolar disorder, particular bipolar II disorder, is under diagnosed (Angst, 2006; Angst et al., 2011; Angst and Cassano, 2005; Benazzi, 1997; Berk et al., 2006; Ghaemi et al., 2000, 1999). This narrative review aims to provide insight on the prevalence, course, clinical characteristics, costs and treatment of bipolar disease.

evidence to suggest a significant portion of patients who have subthreshold hypomanic symptoms at the time of presentation with a major depressive episode subsequently undergo diagnostic conversion to bipolar disorder (Fiedorowicz et al., 2011). In a recent study, of 550 participants with major depressive disorder, a diagnostic change to bipolar disorder was noted in 108 (19.6%) of participants. Furthermore, in this study a number of subthreshold hypomanic symptoms predicted progression to bipolar disorder (Fiedorowicz et al., 2011). In the DSM-IV, for a mixed episode, patients must meet criteria for both a manic episode and a major depressive episode (except for duration) nearly every day during at least a 1-week period. In contrast, in the most recent revision to the DSM-5, the threshold for mixed episodes has been reduced substantially (American Psychiatric Association). There is now a ‘‘with mixed features’’ specifier, with the current revision stating that this mixed features specifier ‘‘applies in episodes where subthreshold symptoms from the opposing pole are present during a full mood episode. While these concurrent ‘‘mixed’’ symptoms are relatively simultaneous, they may also occur closely juxtaposed in time as a waxing and waning of individual symptoms of the opposite pole (i.e., depressive symptoms during hypo/manic episodes and vice versa)’’ (American Psychiatric Association). In addition to being incorrectly diagnosed with depressive illness, patients with bipolar disorder may also be incorrectly diagnosed with other psychiatric illnesses, most commonly anxiety disorder, schizophrenia and borderline or antisocial personality disorders (Young, 2009).

3. Delayed diagnosis 2. What is the true prevalence of bipolar disorder? Depression is a relatively easy condition to diagnose, whereas bipolar disease is often more difficult to diagnose (Angst, 2006; Angst et al., 2011; Angst and Cassano, 2005; Benazzi, 1997; Berk et al., 2006; Ghaemi et al., 2000, 1999). Any lack of information on hypomanic symptoms will result in depression being diagnosed, and patients with bipolar disorders often present with depressive features that are mistaken for unipolar depression (Angst, 2006; Angst et al., 2011; Angst and Cassano, 2005; Benazzi, 1997; Berk et al., 2006; Ghaemi et al., 2000, 1999). For example, in a study conducted in a private psychiatric setting, of the 203 consecutive patients presenting with a DSM-IV major depressive episode, 103 (50.73%) patients were found to have unipolar depression, with 92 (45.32%) diagnosed with bipolar II disorder and 8 (3.94%) with bipolar I disorder. Moreover, research has shown that between 30% and 40% of those with bipolar disorder have previously received an incorrect diagnosis of unipolar depression (Berk et al., 2006; Ghaemi et al., 2000, 1999; Hirschfeld et al., 2003; Manning et al., 1997). In the BRIDGE study, of 5693 patients presenting with a major depressive episode, 16% met DSM-IV criteria for bipolar I disorder, with 47% meeting bipolarity specifier criteria (Angst et al., 2011). With the publication of the DSM-5 in May 2013, the proportion of patients with unrecognized bipolar disorders may be reduced (American Psychiatric Association). Currently, patients presenting with a major depressive episode and some hypomanic or manic symptoms, but not enough to meet the DMS-IV criteria for a mixed episode, may be diagnosed as having unipolar depression. However, there is

Patients with bipolar disorder may experience up to 10 years’ of symptoms before their hypomania is identified (Angst, 2006; Berk et al., 2006; Hirschfeld et al., 2003). There are a number of reasons for delayed diagnosis, including difficulties recognizing initial hypomanic symptoms, particularly in early adolescence when up to two thirds of cases of bipolar disorder first appear (Angst, 2006). Additionally, patients tend to seek help for depression, with hypomania infrequently perceived by the individual involved as being pathological and thus not reported, and observation periods are often too short to identify bipolar disorder, as it is diagnosed on the lifetime occurrence of mania or hypomania (Angst, 2006). There are a number of deleterious consequences of delayed diagnosis. These include prolonged patient suffering due to uncontrolled symptoms and a worse prognosis (Angst and Cassano, 2005). Earlier detection and treatment of bipolar disorder is expected to reduce the risk of serious events such as suicide, which is particularly important given that the lifetime risk of at least one suicide attempt has been reported in 25–50% of patients with bipolar disorder (Jamison, 2000). There is evidence to suggest that when receiving the appropriate treatment for bipolar disorder, such as maintenance lithium treatment, this risk of suicide is reduced (Baldessarini and Jamison, 1999). Moreover, if diagnosed with unipolar depression rather than bipolar disorder, patients are likely to be started on treatment with antidepressants, which has been reported to lead to manic switch, a mixed state or rapid cycling in bipolar disorder patients when not given in combination with appropriate mood stabilizing therapy (Bowden, 2005).

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4. Comorbidities in bipolar disorder Bipolar disorder is very frequently associated with significant comorbidity, with one study showing that bipolar disorder may be twice as likely to occur with another axis I psychiatric disorder as to occur alone (McElroy et al., 2001). General medical conditions also occur more frequently in patients with bipolar disorder (Kilbourne et al., 2004). Common comorbid diseases include pain disorders, cardiovascular disease, obesity, substance abuse, eating disorders, anxiety disorders, impulse control disorders, personality disorders and migraine (McIntyre et al., 2004; Oswald et al., 2007). Patients with bipolar disorder are also significantly more likely to have hyperglycemia, diabetes, angina, dyslipidaemia, hypertension, and metabolic syndrome than the general population (Centorrino et al., 2009). The issue of substance abuse is of particular importance among patients with bipolar disorder, with rates of substance abuse significantly higher in this patient population than in the general population (Brady and Lydiard, 1992; Sonne et al., 1994). More specifically, rates of alcohol use have been reported in 21.4–54.5% of patients with bipolar disorder (Pini et al., 2005), and cannabis use is also highly prevalent, with such comorbid substance abuse associated with worse treatment response and clinical outcomes (De Hert et al., 2011). Notably, there is some evidence that in many patients with bipolar disorder, substance abuse precedes the development of bipolar disorder (Strakowski et al., 1998). It has been reported that in patients with substance abuse disorders and comorbid bipolar disorder, approximately 60% developed substance abuse prior to the onset of bipolar disorder (Strakowski and DelBello, 2000). A 425-patient study showed that, among patients with substance abuse disorder, 3% had comorbid mania (Compton et al., 2000), and other studies have reported that rates of bipolar disorder are elevated five to eight times in patients with substance abuse disorders (Kessler et al., 1997; Regier et al., 1990). Persons with mood disorders and anxiety are twice as likely to suffer from substance abuse disorders and conversely, persons diagnosed with substance abuse disorders are roughly twice as likely to suffer from mood and anxiety disorders compared with the general population (Conway et al., 2006). One survey revealed that, 40% of those with substance use disorders had a comorbid mood disorder compared with a prevalence of approximately 20% among all respondents (Conway et al., 2006). This issue is a particularly difficult one to unravel, as while substance abuse can lead to mental illness, mental illness can also lead to substance abuse, and substance abuse disorders and mental illness have common risk factors. Moreover, bipolar disorder often exists as a secondary diagnosis, or undiagnosed, in patients with other primary diagnoses, including migraine, borderline personality disorder, post-traumatic stress disorder and obsessive compulsive disorder (Antonaci et al., 2011; Compton et al., 2000; Conway et al., 2006; Gross et al., 2002; Marcinko and Vuksan-Cusa, 2009; Ruscio et al., 2010). In one study of individuals with lifetime DSM-IV/CIDI obsessive compulsive disorder, 90% of respondents met criteria for another lifetime DSM-IV/CIDI disorder (Ruscio et al., 2010). The most common comorbid conditions were anxiety disorders (75.8%), followed by mood disorders (63.3%). This study found that the proportion of comorbid cases where obsessive compulsive disorder began before the mood disorder (45.6%) was very similar to the proportion where the mood disorder began first (40.2%) (Ruscio et al., 2010). Another comorbid condition frequently found with bipolar disorder is borderline personality disorder, a condition which is difficult to treat and associated with substantial comorbidity with other axis I disorders (Marcinko and Vuksan-Cusa, 2009). Importantly, there exists overlap of symptoms between borderline personality disorder and bipolar II disorder, in both the depressive and hypomanic mixed states, making these two conditions difficult to differentiate; bipolar

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disorder may be mistaken for symptoms of borderline personality disorder, thus masking the bipolar disorder (Gross et al., 2002). The high prevalence of residual symptoms in bipolar disorders and the unstable and partly remitting course of borderline personality disorder make it even more difficult to distinguish the two disorders (Judd et al., 2003; Marcinko and Vuksan-Cusa, 2009; Paykel et al., 2006). Furthermore, studies have reported that as many as 20% of patients with borderline personality disorder meet criteria for bipolar I disorder (Comtois et al., 1999; Gross et al., 2002). Other conditions that have been shown to be associated with a higher incidence of bipolar disorder than in those without such conditions include migraine, particularly migraine with aura, and psoriasis (Antonaci et al., 2011; Han et al., 2011). 5. Off-label prescription of bipolar disorder medications may indicate a higher than estimated prevalence of BD Off-label prescribing of psychiatric medications (i.e., prescribing medications outside their approved indication) is widespread in clinical practice (Radley et al., 2006). For instance, antipsychotic agents and other mood stabilizing agents have been reported to be used off-label in post-traumatic stress disorder, obsessive compulsive disorder, personality disorders and substance abuse disorder (Rowe, 2007). In one cross-sectional survey of hospital inpatients aged 18–65 years, interviews with consultant psychiatrists regarding off-label usage of mood stabilizers were carried out (Haw and Stubbs, 2005). A total of 249 inpatients were identified, of whom 75 (30.1%) were receiving mood stabilizers. Four patients were receiving mood stabilizers for licensed indications, with the remaining 71 patients receiving medication for unlicensed indications, with the most common indication being prophylaxis of mood swings (48/71, 67.6% patients). Furthermore, in borderline personality disorder, pharmacological treatment is used for symptoms of affective dysregulation (Bellino et al., 2008). With the introduction of the atypical antipsychotic agents, the use of off-label agents for borderline personality disorder has increased further (Perrella et al., 2007). Often ‘‘off-label treatment’’ with bipolar disorder medications may become ‘‘in label’’ when a clinician does not limit the diagnosis to the primary disease. For instance, patients with borderline personality disorders or substance use disorders often meet the criteria for bipolar disease on top of their main diagnosis. Indeed, there is a substantial body of evidence highlighting the frequent comorbidity of bipolar disorder, often as a secondary diagnosis, in patients with disorders such as borderline personality disorder, posttraumatic stress disorder, obsessive compulsive disorder and substance abuse disorders, amongst others (Freeman et al., 2002; Fyer et al., 1988; McElroy, 2004; Sagman and Tohen, 2009; Zanarini et al., 1998). Considerable evidence also exists regarding the prevalence of off-label prescribing of mood stabilizers and antipsychotics among patients with these conditions (Lieb et al., 2010). It is therefore conceivable that a potentially substantial proportion of these patients receiving so-called ‘off label drugs’ for affective symptoms, may in fact have undiagnosed comorbid bipolar disorder as a secondary diagnosis.

6. Premorbid personality Kraepelin (1921) was among the first authors to highlight the importance of enduring personality characteristics, as the underlying ground from which affective states often stem (Kraepelin, 1921). Kraepelin observed that affective temperaments occurred in the premorbid histories of most of manic-depressive probands who returned to their basic temperament rather than to ‘normality’ on remission. Hence, manic, irritable, depressive and cyclothymic

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personalities were the temperamental bases of the full-blown forms of the illness. Of interest, such temperaments, without progression to full-blown illness, were over-represented in the biologic relatives of manic-depressive probands (Kraepelin, 1921). Another study, conducted by Frey, studied premorbid personalities in 65 subjects with major depressive disorder and 45 individuals with bipolar disorder (Frey, 1977). This study observed that patients with major depressive disorder scored higher than bipolar disorders in the scale representing Tellenbach’s ‘‘melancholic type’’, corresponding to being orderly, strenous, and conscientious. Conversely, patients with bipolar disorders showed more extroversion than patients with major depressive disorder (Frey, 1977). Hecht studied the relationship between premorbid personality and subtypes of affective disorder in 52 patients with unipolar depression or bipolar II disorder, 32 patients with bipolar I disorder and 39 control subjects (Hecht et al., 1997). Expert rating of ‘‘typus melancholicus’’ features were found to be more pronounced in unipolar depression/bipolar II disorder than in bipolar I disorder and controls. ‘‘Typus manicus’’ features were also distinguished between both clinical groups, whereas anxious–insecure features were not significantly different between the groups of patients. The authors concluded that premorbid features of ‘‘typus manicus’’ and ‘‘typus melancholicus’’ predicted a predominant manic and a predominant depressive course of an affective disorder, respectively (Hecht et al., 1997). Quilty and colleagues examined the personality predictors of bipolar disorder symptoms, in a psychiatric sample (N¼370; 45% women; mean age 39.50 years), conceptualized as one-dimensional (bipolarity) or two-dimensional (mania and depression) (Quilty et al., 2009). In the monodimensional model, bipolar symptoms were predicted by Neuroticism and (negative) Agreeableness. In the bi-dimensional model, depression was associated with Neuroticism and (negative) Extraversion, whereas mania was associated with Neuroticism, Extraversion and (negative) Agreeableness (Quilty et al., 2009). A study conducted by von Zerssen and colleagues observed a statistically significant association of the ‘affective types’ of premorbid personality (‘melancholic type’ and ‘manic type’) with affective disorders and the ‘neurotoid types’ (‘anxious insecure type’ and ‘nervous tense type’) with non-affective disorders (von Zerssen et al., 1994). A marked preponderance of the ‘manic type’ of personality was found in bipolar I patients, particularly pronounced in those with a predominantly manic course of the disorder; whereas the ‘melancholic type’ of personality prevailed in bipolar II and unipolar depressive patients. Koszewska and Rybakowski assessed the personality traits in 108 patients with bipolar disorders with (n¼32) or without (n¼28) mixed state and with and without rapid cycling, using the Neuroticism, Extraversion, and Openness Personality-fivefactor inventory (NEO-FFI) (Koszewska and Rybakowski, 2008). Ratings were correlated with clinical data of the course of bipolar disorders and neuroticism was found to be significantly higher in patients with mixed state compared with patients without mixed state history. No difference in personality measures were revealed between patients with or without rapid cycling. These results suggest that high neuroticism in bipolar patients may be associated with a predisposition to mixed state but not to rapid cycling .(Koszewska and Rybakowski, 2008) Srivastava and Ketter reviewed the evidence suggesting that personality and temperament contributed to enhanced creativity in individuals with bipolar disorder, a theory that has been supported by studies showing that certain personality/temperamental traits are not only common in patients with bipolar disorder and creative individuals but also correlate with measures of creativity (Srivastava and Ketter, 2010). The authors suggest based on studies using three personality/temperament measures (the NEO inventory, the MyersBriggs Type Indicator [MBTI] and the Temperament Evaluation of

the Memphis, Pisa, Paris, and San Diego Autoquestionnaire [TEMPSA]), that changeable (increased TEMPS-A–cyclothymia) and at times negative (increased NEO-neuroticism) personalities and openminded (increased NEO-openness) and intuitive (increased MBTIintuition) cognition may contribute importantly to enhanced creativity in patients with bipolar disorder (Srivastava and Ketter, 2010). ¨ Lonnqvist and colleagues explored the premorbid personality traits Neuroticism, Extraversion, and Disinhibition in individuals later diagnosed with psychotic disorders and also showed an association ¨ between premorbid Extraversion and bipolar disorder (Lonnqvist et al., 2009).

7. Prodromal, residual and sub-syndromal symptoms Bipolar disorder is considered an episodic disease, marked by relatively short episodes of manic, hypomanic or depressive episodes, but evidence suggests that bipolar disorder is in fact associated with greater chronicity than is implied by this episodic description (Judd et al., 2002; Prien and Kocsis, 1995; Solomon et al., 2010). A high proportion of patients with bipolar disorder have prodromal or residual symptoms during intervals between episodes (Fagiolini et al., 2005b; Kaya et al., 2007; Keitner et al., 1996; Prien and Kocsis, 1995; Wells et al., 1992), and it has been estimated that between 20% and 35% of patients do not fully recover from any given episode (American Psychiatric Association, 1993; Prien and Kocsis, 1995). Keitner and colleagues evaluated the prodromal and residual symptoms of mania and depression in 74 patients with bipolar I disorder and observed that 78% of the patients reported prodromal depressive symptoms and 87% reported prodromal manic symptoms (Keitner et al., 1996). More than half of the patients disclosed residual symptoms of depression (54%) and mania (68%). Cognitive symptoms were the most common symptoms reported by patients, followed by mood symptoms (Keitner et al., 1996). A study conducted by Sierra and colleagues reviewed the literature to describe the manic and depressive prodromal symptoms associated with relapse (Sierra et al., 2007). They demonstrated that the most common depressive prodromes are mood changes, psychomotor symptoms and increased anxiety; the most frequent manic prodromes are sleep disturbances, psychotic symptoms and mood changes. They also noted that certain interventions have proven effective to prevent prodromal symptoms evolving into a full diagnosis and suggest that learning detection, coping strategies and idiosyncratic prodromes are elements that should be incorporated into daily clinical practice with bipolar patients. Likewise, residual symptoms are as important, due to their significant impact on patient quality of life and the risk of recurrence and chronicity (Sierra et al., 2007). One study that clearly demonstrates this chronicity is a study in 146 patients with bipolar I disorder conducted over a mean follow-up period of 12.8 years (Judd et al., 2002). In this study, patients were found to be symptomatically ill for 47.3% of the weeks assessed during the follow-up period. Depressive symptoms were more frequent than either manic/hypomanic symptoms or cycling/ mixed symptoms. Importantly, sub-syndromal depressive and hypomanic symptoms were three times more frequent than syndromal-level major depressive and manic symptoms, highlighting the importance of such sub-syndromal symptoms (Judd et al., 2002). These are symptoms that have been largely ignored previously, leading to substantial underestimation of the true burden of this disease. In a similar study conducted in patients with bipolar II disorder, results were analogous and again highlighted the chronicity of bipolar disorder (Judd et al., 2003). More specifically, in this 86-patient study with a mean of 13.4 years’

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follow-up, patients were found to be symptomatic for 53.9% of the follow-up weeks, with depressive symptoms dominating over hypomanic symptoms and cycling/mixed symptoms (Judd et al., 2003). Further evidence comes from the Bipolar Disorder Center for Pennsylvanians study (n ¼515), in which 29% of those who were symptomatic at study entry did not achieve recovery (at least 8 weeks with CGI of 1 or 2) within the 24-month study period. Of those who did meet these recovery criteria, 40% had a new episode during the study (Fagiolini et al., 2009). Moreover, in the STEP-BD study, only 58% of patients achieved recovery within 24 months (Perlis et al., 2006), of whom 49% experienced recurrences. Finally, a large study including a total of 219 patients with bipolar I disorder who had 1208 mood episodes of the study period (median of 4 episodes per subject), investigated the time to recovery after a mood episode (Solomon et al., 2010). In this study, the median duration of bipolar I mood episodes was 13 weeks. Over the first five mood episodes for each individual, only 41–59% had recovered at 3 months, and at 6 months, approximately 30% of patients had not recovered (Fig. 1). Moreover, more than 10% of patients had still not recovered at 2 years, and between 5% and 10% of patients had not recovered by 5 years.

8. The natural course of bipolar disorder Valuable data on the natural length of psychiatric disorders were published before the availability of effective treatments. For instance, the Iowa 500 study examined 200 inpatients with schizophrenia, 100 with bipolar disorder and 225 with major depressive disorder consecutively admitted to the Iowa Psychopathic Hospital between 1934 and 1944 (Clancy et al., 1974). Prior to the introduction of effective treatments, manic episodes lasted between 7 and 13 months. However, for patients who were followed after 1945, at which point there was clear evidence of effective treatment (e.g., electroconvulsive therapy), episodes became much shorter and were usually terminated 1.8–2.7 months from their onset (Clancy et al., 1974; Winokur and Tsuang, 1996). As reviewed by Angst and Sellaro (Angst and Sellaro, 2000), in 1881 Mendel reported on the length of manic episodes in 43 patients with bipolar disorder, for whom a median duration of 5–6 months was observed. Similarly, in 1924 Panse examined the follow up of 205 hospitalized patients with bipolar disorder and found a mean length of 7 months for manic and depressive episodes and in 1929 Wertham investigated 1000 male and 1000 female patients at their first admissions for mania and reported a mean duration of symptoms of 4–6 months (Angst and Sellaro, 2000). Other studies suggest that the length of episodes were

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shorter; Angst and Sellaro estimated from published histograms that the median duration of episodes in patients with bipolar disorders were 4–6 months (Angst and Sellaro, 2000), whereas a publication by Rennie in 1942 found that there was an increase in length for repeated manic episodes, with the first episode lasting 3.5 months, the second 5.2 months, the third 5.8 months, and the fourth and fifth even longer (Angst and Sellaro, 2000). Finally, in 1954 Kinkelin described the course of bipolar disorder in 347 patients and reported a mean length of depressive episodes ranging from 3.5 to 8.4 months, and of manic episodes from 4 to 11.6 months (Angst and Sellaro, 2000). Apart from the availability or lack of effective treatments, the differences in the average duration of episodes from one study to another are likely accounted for by the differences in illness severity, depending on the setting where patients were admitted/recruited. Nonetheless, it is unquestionable that the availability of new treatments has shortened the mean duration of episodes.

9. Implications for treatment The increasingly apparent chronicity of bipolar disorders, both bipolar I and bipolar II, have important implications for treatment. The initial treatment given for bipolar disorder is considered acute treatment, given to achieve remission of the acute symptoms of the current, presenting episode (Prien and Kocsis, 1995). The primary treatment for the acute phase of bipolar disorder, for both depressive and manic episodes, is mood stabilizers, commonly lithium or valproate semisodium, as well as atypical antipsychotics (Fountoulakis et al., 2005; Sachs et al., 2000). Most patients will at some stage require combination therapy, for instance, a classic mood stabilizer and an antipsychotic during manic episodes. If antidepressants are required, these are only recommended when used in combination with antimanic agents, to reduce the risk of switching (Fountoulakis et al., 2005). In our clinical practice, we never consider the use an antidepressant (not even in patients without a full blown bipolar disorder diagnosis) before all symptoms of agitation, activation, impulsivity, dysphoria, tension are cleared, i.e. before any manic spectrum symptom or sign has disappeared (Fagiolini et al., 2002). Conversely, we will consider the use of an antidepressant in combination with a mood stabilizer or an antipsychotic, in patients whose current symptoms are mainly represented by low energy, psychomotor retardation, hypersomnia, lack of interest and lack of motivation. Remission from the acute phase of bipolar disorder is defined in various ways, often considered as a return to the individual’s well state, but in research is usually defined as

Fig. 1. Time to recovery from the first 5 prospectively observed mood episodes. The survival curves depict the duration of the first five prospectively observed mood episodes and are based on cumulative recovery probabilities (Kaplan–Meier estimates). The five curves are similar, indicating that time to recovery in the sample as a whole was consistent across multiple mood episodes. Reproduced with permission from Archives of General Psychiatry. 2010;67(4):339–347. http://dx.doi.org/10.1001/ archgenpsychiatry.2010.15..

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when an individual no longer meets diagnostic syndrome criteria—which often means that minor, sub-syndromal symptoms may still exist (Prien and Kocsis, 1995). As has been discussed in the preceding section of this review, for many patients, true remission may not be achieved for many weeks, months, or even years, suggesting that so-called ‘acute treatment’ may need to be continued, and adjusted, over a long period. After a patient has been deemed to have recovered, maintenance treatment is usually given. This should comprise an antimanic agent, with some patients also requiring maintenance antidepressant therapy (Fountoulakis et al., 2005). Lamotrigine may be a valuable option to prevent depressive episodes (Fountoulakis et al., 2005; Sachs et al., 2000). However, even when a clinical response or even remission is seen, this may not always mean that the acute episode has actually and completely resolved, rather the treatment may be masking an ongoing biological process that may ‘re-emerge’ upon treatment discontinuation (Prien and Kupfer, 1986). This period following apparent symptom resolution can be considered a period where continuation therapy should be considered, that is continuation of the treatment given for the acute phase, with such therapy recommended to continue for at least 4 months, or longer if there are symptomatic breakthroughs (Prien and Kocsis, 1995; Prien and Kupfer, 1986).

10. The cost of bipolar disorder Despite advances in treatment, bipolar disorder remains associated with high psychosocial and functional disability, with less than 20% of the total economic costs of bipolar disorder associated with direct treatment costs (Goldberg and Ernst, 2002). The indirect costs of bipolar disorder, such as loss of productivity and increased mortality, are considerable (Centorrino et al., 2009), with a large portion of the economic burden of bipolar disorder attributed to uncontrolled symptoms, due to inappropriate treatment, lack of treatment and delayed treatment. Notably, the WHO burden of disease study ranked bipolar disorder 6th worldwide in cause of medical disability (Murray et al., 1994). In a 1991 US study, direct costs of bipolar disorder were estimated at $US7 billion, comprising expenses for treatment-related inpatient and outpatient care, as well as non-treatment-related costs, such as use of the criminal justice system, with indirect costs of $US38 billion. These indirect costs included lost productivity of wage earners of $US17 billion and lost productivity costs for individuals lost to suicide of $US8 billion (Wyatt and Henter, 1995). The growing burden of bipolar disorder was demonstrated in a 2009 study, which showed marked increases in both the direct and indirect costs of bipolar disorder compared with the previously discussed 1991 study. These increases were even greater than that expected from inflation alone. In this 2009 study, the total direct costs of bipolar I and II disorders were estimated at $US30.7 billion, with total indirect costs of $US120.3 billion, giving a total cost of $US151.0 billion (Dilsaver, 2011). This study found that direct costs escalated out of proportion (2.2393-fold) to indirect costs (1.6148-fold) (Dilsaver, 2011). Importantly, the authors note that these figures need to be considered significant underestimations of the true cost of bipolar disorders, as the prevalence figures used do not include the full array of bipolar disorders, such as subthreshold cases. The evidence presented in the current review regarding the degree to which the prevalence of bipolar disorders is underestimated supports the authors’ view that the above figures are likely to be significant underestimations of the true cost of bipolar disorders. An Australian study also found bipolar disorder and associated suicide to be associated with substantial direct and indirect costs,

estimating real financial costs to be $AUS1.59 billion in 2003, over $AUS16,000 on average for each of nearly 100,000 Australians with the illness, with direct health system costs estimated at $AUS298million (SANE Australia, 2003). Many studies investigating the costs of bipolar disorders in various settings have found that hospitalization makes up a significant portion of the direct medical costs. In the UK, the total annual NHS cost associated with managing bipolar disorder was estimated at £342 million at 2009/2010 prices, with hospitalization accounting for £207 million of this cost (Young et al., 2011). Additionally, in a Spanish study (n¼ 784), direct costs associated with healthcare resource utilization during manic episodes were high, and the majority of this cost was associated with hospitalization (Tafalla et al., 2010). Furthermore, a 2004 systematic review revealed inpatient costs to be the largest cost contributor in bipolar disorders (Dean et al., 2004). 10.1. Comorbidity increases costs Compared with many other chronic illnesses, including depression and coronary artery disease, bipolar disorder is associated with significantly higher healthcare utilization costs, even after adjustment for age and comorbidity, with costs comparable to those of diabetes (Dean et al., 2004; Williams et al., 2011). Comorbidities in bipolar disorder, both psychiatric and medical, further add to the cost of disease—patients with bipolar disorder use resources for both mental and non-mental healthcare at higher rates and at higher costs than patients without the disorder (Bryant-Comstock et al., 2002). One large (n¼67,862) cohort study found that of total treatment costs in bipolar patients, 33% were bipolar related, with the remaining 67% related to comorbidities (Guo et al., 2008). Furthermore, one retrospective analysis of claims data for 28,531 patients with bipolar disorder that demonstrated a significantly higher prevalence of metabolic comorbidities than in the general population, also found that annual medical service treatment costs for metabolic conditions were twice that of the control cohort (Centorrino et al., 2009). 10.2. Occupational burden In a systematic literature review examining the burden of bipolar disorder, data indicated that the chronicity of bipolar disorder was associated with a debilitating effect on patients (Fajutrao et al., 2009). More specifically, data from Germany revealed that 70% of patients with bipolar disorder were underemployed, and that 72% received disability payments. In Italy, figures were similar, with 63–67% of patients unemployed. UK data highlighted the costs associated with this high level of unemployment among patients with bipolar disorder, with an annual cost of £1510 million unemployment at 1999/2000 prices (Fajutrao et al., 2009). Moreover, among bipolar patients who are employed, the occupational burden is substantial, with significant impact on worker absenteeism and diminished productivity (Goldberg and Ernst, 2002). Research has highlighted the significantly higher costs associated with employees with bipolar disorder compared with those for mental health categories, including alcohol-related and substance-related mental disorders, as well as comorbid physical/ medical conditions (Rajagopalan et al., 2006). In a study involving 761 employees (0.3%) with bipolar disorder and 229,145 eligible employees without bipolar disorder, employees with bipolar disorder were found to cost $US6836 more per year than employees without bipolar disorder, and were more costly in every health benefit cost category (Gardner et al., 2006). Furthermore, employees with bipolar disorder missed an average of 18.9 workdays annually, while

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employees without bipolar disorder missed only 7.4 days annually (po0.05) (Gardner et al., 2006). In a review designed to elucidate the features of bipolar disorder that are associated with treatment difficulties and high treatment costs, results indicated that, despite recent advances in treatment, particularly outpatient therapy, hospitalization still accounts for a substantial portion of direct costs. Moreover, while a variety of outpatient services are becoming increasingly important for bipolar disorder, costs of such care are growing. Indirect costs due to morbidity and premature mortality comprise a large portion of the cost of illness, and lost workdays and inability to work due to the disease cause high morbidity costs. Intangible costs such as family burden and impaired health-related quality of life are common, but it is difficult to quantify the costs of these (Kleinman et al., 2003). 11. Long term outcomes and excess mortality in bipolar disorder Bipolar disorder is a chronic, potentially lethal disease that is associated with poor psychiatric outcome and a high rate of suicide (Baldessarini and Tondo, 2003; Kilbourne et al., 2004). Increased mortality is a major adverse effect in patients with bipolar disorder and many studies have found mortality and suicide mortality rates of approximately 2 and 10 times that of the general population, respectively (Astrup et al., 1959; Bratfos and Haug, 1968; Høyer et al., 2000; Petterson and Arnetz, 1997; Sharma and Markar, 1994; Tsuang et al., 1980; Vestergaard and Aagaard, 1991). Medical risk factors and medical disease are common in bipolar disorder and lead to even greater morbidity and mortality. Many medical problems have been cited in the few reports focused on this population, the most common of which are cardiovascular disease, obesity, diabetes, and thyroid disease (Fagiolini et al., 2005a; Kilbourne et al., 2004; Kupfer, 2005). The accumulation of key medical risk factors related to excessive alcohol, tobacco and drug use lead to the early onset of medical diseases with poor long-term outcomes. In a prospective follow-up of patients followed for at least 22 years, Angst and colleagues demonstrated an increased risk of death from cardiovascular and cerebrovascular disorders and from accidents and intoxication in patients with bipolar disorders compared with patients with non-bipolar depression (Angst et al., 2002). Kilbourne and colleagues studied the prevalence of medical comorbidities in 3709 patients with bipolar I disorder (mean age ¼52713 years) and found that such individuals carry a substantial burden of medical comorbidity, especially diabetes and cardiovascular problems, that can significantly increase their risk of death (Kilbourne et al., 2004). Such comorbidities were also more prevalent and occurred at an earlier age (i.e., 4-8 years earlier) than in the general patient population, suggesting the need for earlier detection and treatment in patients with bipolar disorder. In assessing medical comorbidity in outpatients at Duke University (mean age¼37.1 years), Krishnan and colleagues categorized the medical diagnoses of 1326 patients treated for bipolar disorder from 2001 to 2002 (Krishnan, 2005). The most common comorbid systemic illnesses were endocrine and metabolic diseases (12.7%), nervous system and sense organ diseases (11.1%) and circulatory system diseases (10.5%). Cassidy and colleagues found the prevalence of diabetes among individuals with bipolar disorder was three times higher than in the general population (Cassidy et al., 1999). Furthermore, those bipolar patients with comorbid diabetes had a greater number of lifetime psychiatric hospitalizations than did the non-diabetic subjects. ¨ sby and colleagues identified from an inpatient register Finally, O all patients with a hospital diagnosis of bipolar (n¼15,386) or unipolar (n¼39,182) disorder in Sweden from 1973 to 1995 and linked these cases with the national cause-of-death register to ¨ sby et al., 2001). Overall determine the date and cause of death (O and cause-specific standardized mortality ratios (SMRs) and

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numbers of excess deaths were calculated by 5-year age classes and 5-year calendar periods. For patients with bipolar disorder, the SMRs for suicide were 15.0 for males and 22.4 for females. For all natural causes of death, SMRs were 1.9 for males and 2.1 for females. Most excess deaths were from natural causes. The SMR for suicide was especially high for younger patients during the first years after ¨ sby et al., 2001). the first diagnosis (O

12. Conclusions Bipolar disorder is frequently under-diagnosed, largely as it is difficult to diagnose, and the true prevalence is therefore likely to be much higher than has been estimated in many studies conducted to date. In addition to the diagnostic issues, the true burden of bipolar disorder is further underestimated due to a lack of understanding of the chronicity of the disease and the high prevalence of residual symptoms. Moreover, the high frequency of off-label prescribing of mood stabilizers in particular for disorders in which bipolar disorder is frequently comorbid, suggests that bipolar disorder is often ‘hidden’ in individuals with other primary diagnoses, leading to an even greater underestimation of the true prevalence of this illness, an illness that is costly, both to society and to individuals. Research to help elucidate the true course of bipolar disorder is necessary to help with treatment going forward.

Role of funding source Lundbeck sponsored editorial assistance for the preparation of this manuscript.

Conflict of interest Andrea Fagiolini is a consultant and/or a speaker and/or has received grants from Angelini, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Eli Lilly, Janssen, Lundbeck, Novartis, Otsuka, Sigma Tau. Rocco Forgione is a consultant for Angelini, Lundbeck and Bristol Meyers Squibb. Mauro Maccari, Benedetto Morana, Mario Catena Dell’Osso and Alessandro Rossi declare no conflict of interest. Francesca Pellegrini has received grants from Eli Lilly and Pfizer.

Acknowledgments The authors thank Denis Bilotta and Simone Boniface from inScience Communications, Springer Healthcare who provided editorial assistance for the preparation of this manuscript. This assistance was sponsored by Lundbeck.

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